TAK-875 is a potent, selective and orally bioavailable GPR40 (G protein-coupled receptor 40) agonist with an EC50 value of 0.014μM for human GPR40. GPR40 is highly expressed in pancreatic β cells and β cell lines in humans and rodents, and has also been found in multiple regions of the human brain. TAK-875 demonstrates potent plasma hypoglycemic and insulin-promoting effects in oral glucose tolerance tests of female Wistar fat rats with impaired glucose tolerance, and has been selected as a clinical candidate drug for the treatment of diabetes[1].
In vitro, TAK-875 dose-dependently increased intracellular inositol monophosphate (IP) production and Ca²⁺ levels at 0.1-10µM and 3-30µM in rat insulinoma INS-1 833/15 cells under 1-10mM glucose, and stimulated insulin secretion at 0.001-10µM in the presence of 10mM glucose[2]. TAK-875 at 6.25-100µM for 72h did not alter glucose-stimulated insulin secretion, insulin content, or caspase-3/7 activity in INS-1 833/15 cells[2].
In vivo, intravenous administration of TAK-875 at 1mg/kg in rats resulted in a plasma clearance (CL) of 34.16mL/h·kg, a terminal half-life (t₁/₂λ) of 4.7h, and a steady-state volume of distribution (Vd(ss)) of 208.49mL/kg, whereas oral gavage at 3mg/kg resulted in good absorption, with an AUC0–24h of 65µg·h/mL, a Cmax of 5.77µg/mL, and an oral bioavailability of 76%[1]. TAK-875 (1-10mg/kg; p.o.) significantly improved glucose tolerance and enhanced insulin secretion in type 2 diabetic N-STZ-1.5 rat models[2]. TAK-875 (10mg/kg; p.o.) significantly increased plasma insulin levels and reduced fasting hyperglycemia in male Zucker diabetic fatty rats[2].
References:
[1] Negoro N, Sasaki S, Mikami S, et al. Discovery of TAK-875: A Potent, Selective, and Orally Bioavailable GPR40 Agonist. ACS Med Chem Lett. 2010;1(6):290-294.
[2] Tsujihata Y, Ito R, Suzuki M, et al. TAK-875, an orally available G protein-coupled receptor 40/free fatty acid receptor 1 agonist, enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia in type 2 diabetic rats. J Pharmacol Exp Ther. 2011;339(1):228-237.